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Molecular and Cellular Biology

Ana Andjelković, Amelia Mordas, Lyon Bruinsma, Annika Ketola, Giuseppe Cannino, Luca Giordano, Praveen K Dhandapani, Marten Szibor, Eric Dufour, Howard T Jacobs
Downregulation of Jun N-terminal kinase (JNK) signaling inhibits cell migration in diverse model systems. In Drosophila pupal development, attenuated JNK signaling in the thoracic dorsal epithelium leads to defective midline closure, resulting in cleft thorax. Here we report that concomitant expression of the Ciona intestinalis alternative oxidase, AOX, was able to compensate for JNK pathway downregulation, substantially correcting the cleft thorax phenotype. AOX expression also promoted wound-healing behavior and single cell migration in immortalized mouse embryonic fibroblasts (iMEFs), counteracting the effect of JNK pathway inhibition...
September 17, 2018: Molecular and Cellular Biology
Shota Sasaki, Mizuho Urabe, Tsukasa Maeda, Junko Suzuki, Ryota Irie, Masanori Suzuki, Yasuhiro Tomaru, Masakiyo Sakaguchi, Frank J Gonzalez, Yusuke Inoue
Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4γ was increased in liver-specific Hnf4a -null mice. The increased HNF4γ contained two variants, a known short variant, designated HNF4γ1, and a novel long variant, designated HNF4γ2. HNF4G2 mRNA was highly expressed in small intestine, and the transactivation potential of HNF4γ2 was the strongest among these variants, but the potential of HNF4γ1 was the lowest...
September 17, 2018: Molecular and Cellular Biology
Jyotsna Kumar, Neila L Kline, Daniel C Masison
Polyglutamine (polyQ) aggregates are associated with pathology in protein-folding diseases and with toxicity in the yeast Saccharomyces cerevisiae Protection from polyQ toxicity in yeast by human DnaJB6 coincides with sequestration of aggregates. Gathering of misfolded proteins into deposition sites by protein quality control (PQC) factors has led to a view that PQC processes protect cells by spatially segregating toxic aggregates. Whether DnaJB6 depends on this machinery to sequester polyQ aggregates, if this sequestration is needed for DnaJB6 to protect cells, and the identity of the deposition site are unknown...
September 17, 2018: Molecular and Cellular Biology
Ranjula Wijayatunge, Sam R Holmstrom, Samantha B Foley, Victoria E Mgbemena, Varsha Bhargava, Gerardo Lopez Perez, Kelly McCrum, Theodora S Ross
Deficiency of huntingtin interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop-cassette and a human HIP1 cDNA were knocked-in to intron 1 of mouse Hip1 locus. CMV - Cre -mediated germline excision of the stop-cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre -mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre -mediated, brain-specific HIP1 expression did not rescue the phenotype...
September 17, 2018: Molecular and Cellular Biology
Daniel J Salamango, Jordan T Becker, Jennifer L McCann, Adam Z Cheng, Özlem Demir, Rommie E Amaro, William L Brown, Nadine M Shaban, Reuben S Harris
APOBEC enzymes are DNA cytosine deaminases that normally serve as virus restriction factors, but several members including APOBEC3H also contribute to cancer mutagenesis. Despite importance in multiple fields, little is known about cellular processes that regulate these DNA mutating enzymes. We show that APOBEC3H exists in two distinct subcellular compartments, cytoplasm and nucleolus, and that the structural determinants for each mechanism are genetically separable. First, native and fluorescently tagged APOBEC3H localize to these two compartments in multiple cell types...
September 17, 2018: Molecular and Cellular Biology
Mariam Alsanafi, Samuel L Kelly, Karawan Jubair, Melissa McNaughton, Rothwelle J Tate, Alfred H Merrill, Susan Pyne, Nigel J Pyne
There is controversy concerning the role of dihydroceramide desaturase (Degs1) in regulating cell survival with studies showing that it can both promote and protect against apoptosis. We have therefore, investigated the molecular basis for these opposing roles of Degs1. Treatment of HEK293T cells with the sphingosine kinase inhibitor, SKi (2-( p -hydroxyanilino)-4-( p -chlorophenyl)thiazole)) or fenretinide, but not the Degs1 inhibitor, GT11 (((N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octan-amide)) induced the polyubiquitination of Degs1 (Mr=40-140 kDa) via a mechanism involving oxidative stress, p38 MAPK and Mdm2 (E3 ligase)...
September 17, 2018: Molecular and Cellular Biology
Simone Gallo, Sara Ricciardi, Nicola Manfrini, Elisa Pesce, Stefania Oliveto, Piera Calamita, Marilena Mancino, Elisa Maffioli, Monica Moro, Mariacristina Crosti, Valeria Berno, Mauro Bombaci, Gabriella Tedeschi, Stefano Biffo
The translational capability of ribosomes deprived of specific non-fundamental ribosomal proteins may be altered. Physiological mechanisms are scanty and it is unclear whether free ribosomal proteins can crosstalk with the signaling machinery. RACK1 (Receptor for Activated C Kinase 1) is a highly conserved scaffold protein, located on the 40S subunit near the mRNA exit channel. RACK1 is involved in a variety of intracellular contexts, both on and off the ribosomes, acting as a receptor for proteins in signaling like PKCs...
September 10, 2018: Molecular and Cellular Biology
Feng Zhu, Nan Xie, Zhe Jiang, Guodong Li, Liwei Ma, Tanjun Tong
The cellular senescence-inhibited gene (CSIG) is implicated in important biological processes including cellular senescence and apoptosis. Our work showed that CSIG is involved in serine/threonine protein phosphatase PPM1A myristoylation. Previous research has shown, the myristoylation is necessary for PPM1A dephosphorylating Smad2/3. However, the control and the biological significance of the myristoylation remain poorly understood. In this study, we found that CSIG knockdown disturbs PPM1A myristoylation and reduces PPM1A dephosphorylating its substrate Smad2...
September 10, 2018: Molecular and Cellular Biology
Chandrima Ghosh, Leena Sathe, Joel David Paprocki, Valerica Raicu, Madhusudan Dey
Perturbations in endoplasmic reticulum (ER) homeostasis, a condition termed the "ER stress", activate the unfolded protein response (UPR), an intracellular network of signaling pathways. Recently, we have shown that protein kinase Kin1 and its paralog Kin2 in the budding yeast Saccharomyces cerevisiae (orthologs of microtubule affinity-regulating kinase in humans) contribute to the UPR function. These Kin kinases contain a conserved kinase domain and an auto-inhibitory kinase-associated 1 (KA1) domain separated by a long undefined domain...
September 10, 2018: Molecular and Cellular Biology
Rafeeq Mir, Ankita Sharma, Saurabh J Pradhan, Sanjeev Galande
The ubiquitous transcription factor Specificity protein 1 (SP1) is heavily modified post-translationally. These modifications are critical for switching its functions and modulation of its transcriptional activity, DNA-binding and stability. However, the mechanism governing the stability of SP1 by cellular signaling pathways is not well understood. Here, we provide biochemical and functional evidences that SP1 is an integral part of the Wnt signaling pathway. We identified a phosphodegron motif in SP1 that is specific to mammals...
September 4, 2018: Molecular and Cellular Biology
Daniel Triner, Cristina Castillo, Joe B Hakim, Xiang Xue, Joel K Greenson, Gabriel Nuñez, Grace Y Chen, Justin A Colacino, Yatrik M Shah
Myc-associated zinc finger (MAZ) is a transcription factor highly upregulated in chronic inflammatory disease and several human cancers. In the current study, we found that MAZ protein is highly expressed in human ulcerative colitis and colon cancer. However, the precise role for MAZ in the progression of colitis and colon cancer is not well defined. To determine the function of MAZ, a novel mouse model of intestine epithelial specific MAZ overexpression was generated. Expression of MAZ in intestinal epithelial cells was sufficient to enhance inflammatory injury in two complementary models of colitis...
September 4, 2018: Molecular and Cellular Biology
Guido H Wabnitz, Henning Kirchgessner, Beate Jahraus, Ludmila Umansky, Shirish Shenolikar, Yvonne Samstag
While several protein serine-threonine kinases control cytokine production by T-cells, the roles of serine-threonine phosphatases are largely unexplored. Here, we analysed the involvement of protein phosphatase-1α (PP1α) in cytokine synthesis following costimulation of primary human T-cells. SiRNA-mediated knock-down of PP1α (PP1KD ) or expression of a dominant-negative PP1α (D95N-PP1) drastically diminished IL-10 production. Focusing on a key transcriptional activator of human IL-10, we demonstrate that nuclear translocation of NF-kB was significantly inhibited in PP1KD or D95N-PP1 cells...
September 4, 2018: Molecular and Cellular Biology
Yubin Luo, Bettina Grötsch, Nicole Hannemann, Maria Jimenez, Natacha Ipseiz, Ozge Uluckan, Nengyu Lin, Georg Schett, Erwin F Wagner, Aline Bozec
Inflammatory responses require mobilization of innate immune cells from the bone marrow. The functionality of this process depends on the state of the bone marrow microenvironment. We therefore hypothesized that molecular changes in osteoblasts, which are essential stromal cells of the bone marrow microenvironment, influence the inflammatory response. Here, we show that osteoblast-specific expression of the AP-1 transcription factor Fra-2 (Fra-2Ob-tet ) induced a systemic inflammatory state with infiltration of neutrophils and pro-inflammatory macrophages into the spleen and liver as well as increased levels of pro-inflammatory cytokines, such as IL-1β, IL-6 and GM-CSF...
September 4, 2018: Molecular and Cellular Biology
Vitalay Fomin, Patricia Richard, Mainul Hoque, Cynthia Li, Zhuoying Gu, Mercedes Fissore-O'Leary, Bin Tian, Carol Prives, James L Manley
A GGGGCC repeat expansion in the C9ORF72 ( C9 ) gene is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Several mechanisms have been proposed to account for its toxicity, including the possibility that reduced C9 protein levels contribute to disease. To investigate this, we examined the effects of reduced C9 levels in several cell systems. We first show that C9 knockdown (KD) in U87 glioblastoma cells results in striking morphological changes, including vacuolization and alterations in cell size...
August 27, 2018: Molecular and Cellular Biology
Angel F Corona Velazquez, William T Jackson
Autophagy is an evolutionary conserved, degradative process from single cell eukaryotes, such as S. cerevisiae, to higher mammals, such as humans. The regulation of autophagy has been elucidated through the combined study of yeast, C. elegans , mice, D. melanogaster, and humans. MTOR, the major negative regulator of autophagy, and activating nutrient kinases, such as AMPK, interact with the autophagy regulatory complex: ULK1/2, RB1CC1, ATG13, and ATG101. The ULK1/2 complex induces autophagy by phosphorylating downstream autophagy complexes, such as the BECN1 PIK3 signaling complex that leads to the creation of LC3+ autophagosomes...
August 20, 2018: Molecular and Cellular Biology
E W Cloer, P F Siesser, E M Cousins, D Goldfarb, D D Mowrey, J S Harrison, S J Weir, N V Dokholyan, M B Major
Cancer-derived loss-of-function mutations in the KEAP1 tumor suppressor gene stabilize the NRF2 transcription factor, resulting in a pro-survival gene expression program that alters cellular metabolism and neutralizes oxidative stress. In a recent genotype-phenotype study, we classified 40% of KEAP1 mutations as ANCHOR mutants. By immunoprecipitation, these mutants bind more NRF2 than wild-type KEAP1 and ubiquitylate NRF2, but are incapable of promoting NRF2 degradation. BioID-based protein interaction studies confirmed increased abundance of NRF2 within the KEAP1 ANCHOR mutant complexes with no other statistically significant changes to the complexes...
August 20, 2018: Molecular and Cellular Biology
Yueshui Zhao, Xin Li, Li Yang, Kristin Eckel-Mahan, Qingchun Tong, Xue Gu, Mikhail G Kolonin, Kai Sun
Adipose-derived VEGF-A stimulates functional blood vessel formation in obese fat pads which in turn facilitates healthy expansion of the adipose tissue. However, the detailed mechanism(s) governing the process remains largely unknown. Here, we investigated the role of sympathetic nervous system activation in the process. To this end, we induced overexpression of VEGF-A in an adipose tissue-specific doxycycline (Dox)-inducible transgenic mouse model for a short period of time during high fat-diet (HFD) feeding...
August 20, 2018: Molecular and Cellular Biology
Takashi Moriguchi, Tomofumi Hoshino, Arvind Rao, Lei Yu, Jun Takai, Satoshi Uemura, Kazue Ise, Yasuhiro Nakamura, Kim-Chew Lim, Ritsuko Shimizu, Masayuki Yamamoto, James Douglas Engel
Transcription factor GATA3 plays vital roles for inner ear development, while regulatory mechanisms controlling its inner ear-specific expression are undefined. We demonstrate that a cis -regulatory element lying 571-kb 3' to the Gata3 gene directs inner ear-specific Gata3 expression, which we subsequently refer to as the Gata3 otic vesicle enhancer (OVE). In transgenic murine embryos a 1.5-kb OVE-directed LacZ reporter (TgOVE-LacZ ) exhibited robust LacZ expression specifically in the otic vesicle (OV), an inner ear primordial tissue, and its derivative semicircular canal...
August 20, 2018: Molecular and Cellular Biology
Jo Hae Park, Kunsoo Rhee
The involvement of cell division in cellular differentiation has long been accepted. Cell division may be required not only for the expansion of a differentiated cell population but also for the execution of differentiation processes. Nonetheless, knowledge regarding how specific differentiation processes are controlled in a cell division-dependent manner is far from complete. Here, we determined the involvement of cell division in neuronal differentiation. We initially confirmed that cell division is an essential event for the neuronal differentiation of P19 embryonic carcinoma cells...
August 13, 2018: Molecular and Cellular Biology
Asen Bagashev, Elena Sotillo, Chih-Hang Anthony Tang, Kathryn L Black, Jessica Perazzelli, Steven H Seeholzer, Yair Argon, David M Barrett, Stephan A Grupp, Chih-Chi Andrew Hu, Andrei Thomas-Tikhonenko
We have previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing VSV-G tags. These lines were negative by live-cell flow cytometry with an anti-VSV-G antibody and resistant to killing by VSV-G directed antibody-drug conjugates (ADC), suggestive of a defect in surface localization...
August 13, 2018: Molecular and Cellular Biology
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